A predictive multiscale computational tool for simulation of lung absorption and pharmacokinetics and optimization of pulmonary drug delivery Project Summary/Abstract: Pulmonary drug delivery via oral inhalation is increasingly used for both treatment of lung diseases (such as asthma and chronic obstructive pulmonary disease) and in delivering drugs to the systemic circulation. To reach the desired effectiveness and safety of orally inhaled drugs, appropriate disposition of drugs in targeted region is essential. Due to complex pharmaceutical and physiological factors involving drug transfer from the administration site to the target region, computational modeling tools are urgently required to provide mechanistic insights of involved delivery processes and to estimate efficacy of pulmonary drug delivery in an accurate and efficient manner. Therefore, in this project, we propose to develop a novel predictive multiscale computational tool to simulate delivery, deposition, dissolution, absorption, distribution, metabolism, excretion, and actions of inhaled drug products within an integral framework of computational fluid dynamics (CFD) and PBPK-PD models. We will (1.) develop multimodal computational models of drug deposition in the entire respiratory tract after oral inhalation; (2.) develop an multi-compartmental model for drug absorption and local PBPK in the lung tissue (which includes a dissolution model and a transport model across the air-blood barrier); (3) develop a whole body PBPK model for drug distribution, metabolism, and excretion after absorption from the respiratory tract; integrate a compartmental absorption and transit model for drug absorption from the gastrointestinal tract (already developed at CFDRC) to explore the contribution of the swallowed drug to drug PK; (4) integrate the computational tool with pharmacodynamics model, airway mechanics model and lung physiology model to account for various dynamic physiological and pathological factors on pulmonary drug delivery and absorption; (5) calibrate and validate the proposed tool for two generic drugs: budesonide and formoterol; (6) conduct parametric simulations of drug delivery, absorption, and PK for brand and generic drugs and evaluate effects of compound physiochemical characteristics, formulations, physiological settings and pathological factors; and (7) develop databases of generic drugs, formulations, devices, physiological settings, and pathological factors for inhalation delivery. The proposed computational tool will provide a mechanism- based virtual platform to investigate interactions between drug delivery systems and physiological systems in various pathological settings, to provide mechanistic insights into key aspects affecting efficacy and safety of inhaled drug products, and to guide optimal designs of pulmonary drug delivery systems. The accomplishment of the novel integrated computational tool will greatly facilitate design of dose regimen and drug development by identifying key biopharmaceutical factors affecting efficacy and safety of inhaled drugs. The software tool will be developed into a commercial product (user-friendly GUI ) aiming at pharmaceutical and biomedical markets to support a variety of pharmaceutical and biomedical applications, including LADME-T investigation, in vitro-in vivo scaling, dose regimen design, optimization of pulmonary delivery systems, and safety and efficacy evaluation for inhaled drug products.